ACTOPRIL

Main information

  • Trade name:
  • ACTOPRIL Tablets 25mg Milligram
  • Dosage:
  • 25mg Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ACTOPRIL Tablets 25mg Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0593/011/002
  • Authorization date:
  • 10-12-1998
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ActoprilTablets12.5mg.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each tabletcontainscaptopril25 mg.

Forexcipients, see6.1.

3PHARMACEUTICALFORM

Tablet.

White, round, flat, uncoated tablets, scored on both sides, 8mmin diameter.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hypertension:Captoprilisindicated forthefirstlinetreatmentofmild to moderatehypertension. In severe

hypertension itshould beused wherestandard therapy isineffectiveorinappropriate.

CongestiveHeartFailure:Captoprilisindicated forthetreatmentofcongestiveheartfailure. Thedrug should beused

togetherwith diureticsand, whereappropriate, digitalis.

4.2Posologyandmethodofadminstration

Fororaladministration only.

Captoprilisbesttaken aboutan hourbeforemealsand should betaken atthesametimeseach day to improve

compliance.

Treatmentwith captoprilshould bestarted atthelowesteffectivedoseand titrated to theindividualaccording to their

needs.

Initiation oftherapyrequires, ifpossible, correction ofsaltand/orbody fluidsdeficiencies, discontinuation ofexisting

diuretictherapy fortwo orthreedaysbeforeACEinhibitorsareintroduced, and useoftheloweststarting dose. Ifthis

isnotpossible, theinitialdoseshould behalfoftherecommended starting dose.

In patientswith malignanthypertension, orseverecardiacinsufficiency, initiation oftherapy and doseadjustment

should beperformed in ahospital.

Mild to moderatehypertension:Thestarting doseis12.5mg twicedaily or25mg daily. Theusualmaintenancedoseis

25mg twicedaily, which can beincreased incrementally every 14 to 28 daysuntilasuitableresponsehasbeen

achieved, to amaximumdoseof50mg twicedaily.

Athiazidediureticmay beadded to Captoprilifasatisfactory responsehasnotbeen achieved. Thedoseofdiuretic

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Severehypertension:In severehypertension wherestandard therapy isineffectiveorinappropriatebecauseofadverse

effects, thestarting doseis12.5mg twicedaily or25mg daily. Thismay beincreased incrementally up to amaximum

of50mg threetimesaday. Captoprilshould beused togetherwith otheranti-hypertensiveagentsbutthedoseofthese

should beindividually titrated.Adaily doseof150mg captoprilshould notnormally beexceeded.

Heartfailure:Captopriltherapy mustbestarted underclosemedicalsupervision. Captoprilshould beintroduced when

diuretictherapy (such asfrusemide40-80mg orequivalent)isinsufficientto controlsymptoms. Astarting doseof

6.25mg or12.5mg may minimiseatransienthypotensiveeffect. Thepossibility ofthisoccurring can bereduced by

discontinuing orreducing diuretictherapy ifpossible, priorto initiating captopril. Theusualmaintenancedoseis25mg,

two orthreetimesaday which can beincreased incrementally, with intervalsofatleast14days, untilasatisfactory

responseisachieved. Theusualmaximumdoseis150mg daily.

Elderly:Thedoseshould betitrated againstblood pressureresponseand keptaslowaspossibleto achieveadequate

control. Sinceelderly patientsmay havereducedrenalfunction and otherorgandysfunctions, itissuggested thatalow

doseofcaptoprilbeusedinitially.

Children:Captoprilisnotrecommended forthetreatmentofmild tomoderatehypertension in children. Experiencein

neonates, particularly prematureinfants, islimited. Becauserenalfunction in infantsisnotequivalentto thatofolder

children and adults, lowerdosesofcaptoprilshould beused with patientsunderclosemedicalsupervision.

Thestarting doseshould be0.3mg perkg bodyweightup to amaximumof6mg perkg bodyweightdaily in divided

doses. Thedoseshouldbeindividualised according to theresponseand may begiventwo to threetimesdaily.

Patientswith renalimpairment:Captoprilin divided dosesof75 to100mg/day waswelltolerated in patientswith

diabeticnephropathy and mild to moderaterenalimpairment(creatinineclearanceatleast30ml/min/l.73m). Patients

with severely impaired renalfunction willtakelongerto reach steady statecaptoprillevelsand willreach higher

steady-statelevelsforagiven daily dosethan patientswith normalrenalfunction. Thesepatientsmay thereforerespond

to smallerorlessfrequentdoses.

Therefore, inpatientswith severerenalimpairment(creatinineclearancelessthan 30 ml/min/1.73m), theinitialdaily

doseshould be12.5mg bd. Thedosecan then betitrated againsttheresponsebutadequatetimeshould beallowed

between dosageadjustments.

When concomitantdiuretictherapy isrequired, aloop diureticratherthan athiazidediureticshould bethediureticof

choice.

Captoprilisreadily eliminated by haemodialysis.

4.3Contraindications

Hypersensitivity to ACEinhibitorsorany oftheconstituentsoftheproduct.

History ofangioneuroticoedemaassociated with previoususeofACEinhibitors.

Hereditary oridiopathicangioneuroticoedema.

Useduring Pregnancy and Lactation.

4.4Special warningsandspecialprecautionsforuse

Precautions:Patientsshould beassessed forrenalfunction priorto thestartoftherapy and atappropriateintervals

during therapy. Captoprilshould notbeused in patientswith aorticstenosisoroutflowtractobstruction.

Aslimited experiencehasbeen obtained inthetreatmentofacutehypertensivecrises,theuseofcaptoprilshould be

avoided in thesepatients.

Warnings:Any adversereactionsto captoprilareusually associated with impaired renalfunction sincethedrug is

mainly excreted by thekidneys.Thedoseused should notexceed theamountneeded foradequatecontroland should

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Hypotension:Aprofound drop in blood pressuremay occur, particularly aftertheinitialdose. In uncomplicated

hypertensivepatients, symptomatichypotension rarely occurs. Occurrenceismorelikely in patientswho havebeen

volumedepleted dueto treatmentwith adiuretic, dietary saltrestriction, dialysis, diarrhoeaorvomiting. Reportshave

mainly been forpatientswith severeheartfailurewith orwithoutassociated renalinsufficiency.

Patientson high dosesofloop diuretics, orwith hyponatraemiaorfunctionalrenalimpairment,aremorelikely to

experiencethiseffect. Treatmentofsuch patientsshould begin underclosemedicalsupervision, (within ahospital

preferred), using lowdosesand carefuldosetitration. Useofdiureticsshould bestopped temporarily ifpossible. These

considerationsarealsoapplicableto patientswith anginapectorisorcardiovasculardisease, (excessivehypotension

could causemyocardialinfarction orcerebrovascularaccident).

In theeventofhypotension, thepatientshould beplaced in asupineposition.

Volumerepletion may berequired (intravenousnormalsaline), ifhypotension occursafterthefirstdose, subsequent

carefuldosetitration with captoprilisnotprecluded aftereffectivemanagement.

Patientswith renovascularhypertension:Patientswith renovascularhypertension and pre-existing bilateralrenalartery

stenosisorunilateralrenalartery stenosisgiven captoprilareatan increased risk ofseverehypotension and renal

insufficiency. Even in patientswith unilateralrenalartery stenosis, renalfunction lossmay beassociated with mild

changesinserumcreatinine.

Treatmentshould beinitiatedin hospitalunderclosemedicalsupervision, using lowdosesand carefuldosetitration.

During thefirstweeksoftreatment, useofdiureticsshould bediscontinued and renalfunction should bemonitored.

Patientswith renalinsufficiency:Patientswith renalinsufficiency may requirereduced orlessfrequentdoses

(inhibition oftherenin-angiotensin-aldosteronesystemmay alterrenalfunction in susceptibleindividuals)and should

betreated with caution. Renalfunction should bemonitored closely, asappropriate, during treatment. Reportsofrenal

failureassociatedwith captoprilhaveoccurred mainly in patientswith severeheartfailureorunderlying renaldisease

(e.g. renalartery stenosis). Increasesin blood ureaand creatinineconcentrationshaveoccurred in somepatientswith

apparently no pre-existing renaldiseasewhen adiureticisused concurrently.

Reduction ofthedoseofcaptopriland/ordiscontinuation ofthediureticmay benecessary. Renalfunction should be

monitored during thefirstweeksoftreatment. Patientstreated with captoprilwho aredialysed with high-flux

polyacrylonitrilemembranesarelikely to sufferanaphylactoid reactions(e.g. facialswelling, flushing, hypotension and

dyspnoea)within afewminutesafterdialysishasbegun. Useofan alternativemembraneoran alternative

antihypertensivedrug isrecommended.

Angioedema:Angioedemaoftheface, extremities, lips,mucousmembranes, tongue, glottisand/orlarynx mayoccur

particularly during thefirstweeksoftreatmentwith ACEinhibitors. Ifaseverecaseofangioedemadevelopsafter

long-termtreatmentwith an ACEinhibitor(occursrarely), treatmentshould bestopped promptly and aproductfrom

anotherclassofdrugsused instead.

Angioedemainvolving thetongue, glottisorlarynx may befatal, and emergency treatment, including thefollowing,

should beprovided;an immediatesubcutaneousinjection of0.3-0.5mladrenalinesolution 1 :1000 orslowintravenous

adrenalinelmg/ml(dilution instructionsto beobserved), electrocardiogramorblood pressurecontrol, hospitalisation

and observation foraminimumof12 to 24 hours. Hospitalisation should bemaintained untilallsymptomshave

disappeared.

Cough:Captopriltreatmentmay beassociated with adry non-productivecough which disappearswhen treatmentis

stopped (seesection 4.8).

Hyperkalaemia:Thismay occurduring thetreatment, particularly ifrenalinsufficiency and/orheartfailurearepresent.

Useofpotassiumsupplementsorpotassium-sparing diureticsmay resultin significantincreasesin plasmapotassium

and arenotrecommended. Serumpotassiumshould bemonitored frequently ifsuch productsareused concomitantly.

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anaesthesiadueto enhancementofotherhypotensivepotentials. Adequatevolumemanagementshould beprovided if

discontinuation ofcaptoprilisimpossible.

Aorticstenosis/Hypertrophiccardiomyopathy:Usewith caution in patientswith obstruction oftheoutflowtractofthe

leftventricle.

Elderly/Children:Seesection 4.2.

Neutropenia/Agranulocytosis:Therisk ofneutropeniaappearsto berelated to doseand producttypedependentand the

patient'sclinicalstatus. Thecondition, which isreversible, israrein uncomplicated patients, butmay occurin patients

with renalimpairmentespecially ifassociated with collagen vasculardisease(e.g. systemiclupuserythematosus,

scleroderma)and treatmentwith immunosuppressives.

Proteinuria:Itmay occurifrenalfunction impairmentpre-existsorrelatively high dosesareused.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

NotRecommended

Potassiumsparing diureticsorpotassiumsupplements:Usewith potassiumsparing diureticsorpotassiumsupplements

isnotrecommended (diuretic-induced potassiumlossisreduced by captopril). Significantincreasein serumpotassium

may resultfromconcurrentuseofpotassium-sparing diuretics(e.g. spironolactone, triamterene, amiloride), potassium

supplements, orpotassiumcontaining saltsubstitutes. Ifhypokalaemianecessitatestheiruse, they should beused with

caution and serumpotassiummonitored frequently.

Precautionforuse

Diuretics:Aftercaptopriltreatmenthasstarted, excessivereduction in blood pressuremay occurin patientsreceiving

diureticsand particularly thosewho arevolume-and/orsalt-depleted. Risk ofhypotensiveeffectsmay bereduced by;

stopping diuretictreatment, increasing volumeorsaltintakebeforeadministration ofcaptopril, starting treatmentwith

lowerdosesofcaptopriland, ifnecessary, increasing dosagewith caution.

Lithium:Excretion oflithiummay bereduced iflithiumand captoprilareadministered concomitantly. Frequent

monitoring ofserumlithiumlevelsshould beperformed.

Anaestheticdrugs:Theeffectofanaestheticagentsmay beenhanced.

Narcoticdrugs/Antipsychotics:Posturalhypotension may occur.

Antihypertensiveagents:Increasethehypotensiveeffectofcaptopril.

Allopurinol, cytostaticorimmunosuppressiveagents, corticosteroidsorprocainamide:Therisk ofleucopeniamay be

increased ifused concomitantly with captopril.

Takeintoaccount

Non-steroidalanti-inflammatorydrugs:theantihypertensiveeffectofcaptoprilmay bereduced by administration ofa

NSAID. An additiveeffecton serumpotassiumincreasehasbeen described when NSAIDsand captoprilareused

concomitantly, whilerenalfunction may bereduced. Such effects, which occurparticularly in patientswith

compromised renalfunction, arein principlereversible.

Antacids:Causereduced bio-availabilityofcaptopril.

Sympathomimetics:Theantihypertensiveeffectsofcaptoprilmay bereduced. Patientsshould becarefully monitored.

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Food:Thebio-availabilityofcaptoprilmay bedecreased.

Concomitantadministration ofACE-inhibitorsand anti-diabeticmedicines(insulin, oralhypoglycaemicagents)may

causean increased blood glucoselowering effectwith ariskofhypoglycaemia. Thisphenomenonmay bemorelikely

to occurduring thefirstweeksofcombined treatmentand in patientswith renalimpairment.

4.6Pregnancyandlactation

No appropriateand wellcontrolled studieshavebeen performed in humans. Foetaland neonatalmorbidity and

mortality may occurwhen ACEinhibitors(thesecan crosstheplacenta)areadministered to pregnantwomen.

Neonatalhypotension, renalfailure, faceorskulldeformitiesand/ordeath havebeen associated with exposureofthe

foetusduring thesecond and third trimesters. Maternaloligohydramnios(indicativeofdecreasing foetalrenalfunction)

hasbeen reported. Reportsoflimb contractures, craniofacialdeformities, hypoplasticlung developmentand intra-

uterinegrowth retardation havebeen associatedwith oligohydramnios. Closeobservation ofinfantsexposed in utero

forhypotension, oliguriaand hyperkalaemiashould becarried out. Ifoliguriaoccurs, treatmentconsistsofsupportof

blood pressureand renalperfusion.

Intra-uterinegrowth retardation, prematurity, patentductusarteriosusand foetaldeath havebeen reported, buttheir

relationship to theACEinhibition ortheunderlying maternaldiseaseisunknown.

Theeffectofexposureofthefoetusduring thefirsttrimesteronly isunknown. Ifpregnancy occursduring treatment,

thepregnantwoman should beinformed ofthepossiblehazard to thefoetus.

UseofACEinhibitorsduring breastfeeding by lactating mothersisnotrecommended (ACEinhibitorsmay beexcreted

into breastmilk and theireffectson thenursing infantareunknown).

4.7Effectsonabilitytodriveandusemachines

No studieson theeffectoftheability to drivehavebeen performed. Thepossibility oftheoccurrenceofoccasional

dizzinessorwearinessshould betaken into accountwhen driving oroperating machinery.

4.8Undesirableeffects

Observed sideeffectswith treatmentwith Captopril:

Cardiovascular:SevereHypotension hasbeen observed afterthestartoftreatmentorwhen thedosehasbeen

increased, especially in high risk patients(seesection 4.4).Dizziness, feeling weak, impaired vision with, in rarecases,

disturbanceofconsciousness(syncope)may occur.

Individualincidentsofthefollowing havebeen reported in association with hypotension;tachycardia, palpitations,

arrhythmias, anginapectoris, myocardialinfarction, transientischaemicattacksand cerebralhaemorrhage.

Renal:Intensification ofrenalinsufficiency may occur. Acuterenalfailurehasbeen reported (seesection 4.4).

Respiratory:Induction ofcough in alargenumberofpatientshasbeen reported. Rarereportshavebeen madeof

dyspnoea, sinusitis, rhinitis, glossitis, bronchitisand bronchospasm. Fatalairway obstructionhasoccurred in

angioneuroticoedemainvolving theupperairways.

Gastro-intestinal:Nausea, vomiting, abdominalpain, indigestion, diarrhoea, constipation and dry mouth can occur

occasionally. Rarely cholestaticicterus, hepatitis, pancreatitisand ileushavebeen associated with ACEinhibitor

therapy.

Skin:Allergicand hypersensitivity reactions(e.g. rash, pruritus, urticaria, erythemamultiforme, Stevens-Johnson's

syndrome, toxicepidermicnecrolysis, psoriasis-likeefflorescence, alopecia)arerareand may beaccompanied by

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angioneuroticoedemainvolving thefaceand oropharyngealtissueshasbeen reported (seesection 4.4).

NervousSystem:Headaches, dizziness, wearinessoccuroccasionally. Depression, sleep disorders, paraesthesias,

impotence, balancedisorders, confusion, tinnitus, blurred vision and tastedisturbancesarerare.

Drug/Laboratoryparameters:Reversible(on stopping treatment)increasesinblood ureaand plasmacreatininemay

result, particularly ifrenalinsufficiency, severeheartfailureorrenovascularhypertension ispresent.

Decreasesin haemoglobin, haemocrit, plateletsand whitecellcount, and individualincidentsofagranulocytosisor

pancytopenia, in additionto elevated liverenzymesand serumbilirubin, havebeen reported in afewpatients.

Haemolyticanaemiahasbeen reported in somepatientswith acongenitaldeficiency ofglucose-6-phosphate

dehydrogenase.

4.9Overdose

Overdosagesymptomscompriseseverehypotension, shock, stupor, bradycardia, electrolytedisturbanceand renal

failure.

In casesofoverdosagepatientsshould bekeptunderclosesupervision, (intensivecareunitpreferred). Frequent

monitoring ofserumelectrolytesand creatinineshould beperformed.

Treatmentwilldepend on thenatureand severity. Ifingestion isrecent, measuresshould betaken to preventabsorption

and speed elimination (e.g. gastriclavageand administration ofabsorbentsand sodiumsulphatewithin 30minutesof

drug intake). In casesofhypotension, thepatientshould beplaced in theshockposition and saltand volume

supplementation administered rapidly.

Consideration should begiven to theadministration ofangiotensin II. Atropineshould beusedto treatbradycardiaor

extensivevagalreactions. Useofapacemakercan beconsidered. Dialysismay beused to removecaptoprilfromthe

circulation buthigh-flux polyacrylonitrilemembranesshould beavoided.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ThebenefitsofACEinhibitorsin thetreatmentofhypertension and in heartfailureseemto resultmainly fromthe

suppression oftheplasmarenin-angiotensin-aldosteronesystem. Renin, an endogenousenzymeproduced by the

kidneys, isreleased in to thecirculation and convertsangiotensinogen to angiotensin I, (arelatively inactive

decapeptide). Angiotensin Converting Enzyme, (apeptidyldipeptidase)convertsangiotensin Ito angiotensin II, a

potentvasoconstrictor, which causesarterialvasoconstriction and increased blood pressure. Italso stimulatesthe

adrenalgland to secretealdosterone. Decreased plasmaangiotensin IIresultsfromACEinhibition.

Thisleadsto reduced vasopressoractivity and aldosteronesecretion, thelatterreduction issmallbutmay resultin small

increasesin serumpotassiumconcentrationstogetherwith lossofsodiumand fluid. An increaseinplasmarenin

activityoccurswhen thenegativefeedback ofangiotensin IIon renin secretion stops.

Theconverting enzymealso degradesthekinin peptidebradykinin (apotentvasodepressive)to inactivemetabolites.

Consequently ACEinhibition causesincreased activity ofthecirculating and localkallikrein-kinin system, which

contributesto peripheralvasodilation (prostaglandin systemactivated). Thismechanism, which isresponsiblefor

certain side-effects, may beinvolved in thehypotensiveeffectofcaptopril.

Administration ofcaptoprilto patientswith hypertension reducessupineand standing blood pressureto aboutthesame

extentwithoutacompensating increasein heartrate. Peripheralarterialresistanceisreducedwith eitherno changeor

an increasein cardiacoutput. Thereisan increasein renalblood flowand glomerularfiltration rateisusually

unchanged.

Optimalblood pressurereduction may takeseveralweeksto obtain.

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Rapid increasein blood pressurehasnotbeen associated with abruptcessation oftreatment.

Treatmentiseffectiveeven in patientswith low-renin hypertension.

Antihypertensiveeffectshavebeen studied in differentraces, butmonotherapy produced asmalleraverageresponsein

black hypertensivepatients(generally alow-renin population)than in non-black patients. Thereisno differenceifa

diureticisused.

In patientswith heartfailure, thehaemodynamiceffectsaredueto both arteriolarandvenodilation. Areduction in

systemicvascularresistanceandan increasein venouscapacity occurs, thereby decreasing pre-and after-load. This

resultsin;decreasein leftventricularfilling pressurepulmonary capillary wedgepressure, increased cardiacoutput,

unchanged ordecreased heartrate. Improvementoftheclinicalsignsand symptomsofheartfailureand increased

exercisecapacity willoccur. During long-termtreatment, theseeffectsaremaintained.

5.2Pharmacokineticproperties

Captoprilisrapidly absorbed asan oraldose, with abioavailability ofabout70%afterfasting, thisisdecreased by 30-

40%ifthedrug istaken with food. Itismetabolised chiefly to thedisulfidewith lessthan halftheoraldoseexcreted

unchanged in theurine.

Captoprilisdistributed to mostbody tissueswith thenotableexception ofthecentralnervoussystem. Although the

half-lifeisnotclearly established mostcaptopriliseliminated fromthebody within six hours.

Captoprilisadministered two orthreetimesaday aboutoneortwo hoursbeforemeals. Maximalblood pressure

responseisseen abouttwo to fourhoursaftertheoraldose. Attwo to fourweek intervalsdosescan beincreased until

blood pressureiscontrolled orup to amaximumdoseof150mg perday in divided doses. Beyond thisdosethereisno

furthertherapeuticbenefit.

Becausecaptoprilismainly excreted by thekidney caremustbetaken in patientswith renalinsufficiency wherethe

dosemustbetitrated with theblood pressureresponse.

5.3Preclinical safetydata

Chronicoraltoxicity studiescarried outin animalsshowdrug related toxicity including haematopoiesis, renaltoxicity,

ulceration ofthestomach and changesin theretinalblood vessels.

Atlevelsin excessoftherapeuticdoses, thefollowing conditionswereobserved:anaemia, leucopenia,

thrombocytopeniaand bonemarrowsuppression. Captoprilhasbeen shown to causehyperplasiaofthejuxtaglomerular

apparatusofthekidneysatdoses7 to 200 timesthemaximumrecommended human dose.

Rabbitstudiesshowed gastrointestinalulceration at30 timesmaximumdoseafteraperiod ofonly 5 to 7 days. In atwo

yearstudy in rats, irreversiblechangesin theretinalblood vesselsin adoserelated pattern appeared in thesecond year

ofthestudy.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactosemonohydrate

Pregelatinised maizestarch

Microcrystallinecellulose

Stearicacid

6.2Incompatibilities

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6.3ShelfLife

3 years.

6.4Special precautionsforstorage

Do notstoreabove25°C.

6.5Natureandcontentsofcontainer

AL/PVCblisterpacks.

Pack sizes:10, 56 and 100

6.6Instructionsforuseandhandling

No specialrequirements.

7MARKETINGAUTHORISATIONHOLDER

StadaArzneimittelAG

Stadastrae2-18

D-61118 Bad Vilbel

Germany

8MARKETINGAUTHORISATIONNUMBER

PA593/11/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation: 10 th

December1998

Dateoflastrenewal: 10 th

December2003

10DATEOFREVISIONOFTHETEXT

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